RANK ligand signaling modulates the matrix metalloproteinase-9 gene expression during osteoclast differentiation.

RANK ligand signaling modulates the matrix metalloproteinase-9 gene expression during osteoclast differentiation. Research Abstract Details 

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RANK ligand signaling modulates the matrix metalloproteinase-9 gene expression during osteoclast differentiation. Abstract Text:

Kumaran Sundaram,Riko Nishimura,Joseph Senn,Rimon F Youssef,Steven D London,Sakamuri V Reddy,

Osteoclast differentiation is tightly regulated by receptor activator of NF-kappaB ligand (RANKL) signaling. Matrix metalloproteinase-9 (MMP-9), a type IV collagenase is highly expressed in osteoclast cells and plays an important role in degradation of extracellular matrix; however, the molecular mechanisms that regulate MMP-9 gene expression are unknown. In this study, we demonstrate that RANKL signaling induces MMP-9 gene expression in osteoclast precursor cells. We further show that RANKL regulates MMP-9 gene expression through TRAF6 but not TRAF2. Interestingly, blockade of p38 MAPK activity by pharmacological inhibitor, SB203580 increases MMP-9 activity whereas ERK1/2 inhibitor, PD98059 decreases RANKL induced MMP-9 activity in RAW264.7 cells. These data suggest that RANKL differentially regulates MMP-9 expression through p38 and ERK signaling pathways during osteoclast differentiation. Transient expression of MMP-9 gene (+1 to -1174 bp relative to ATG start codon) promoter-luciferase reporter plasmids in RAW264.7 cells and RANKL stimulation showed significant increase (20-fold) of MMP-9 gene promoter activity; however, there is no significant change with respect to +1 bp to -446 bp promoter region and empty vector transfected cells. These results indicated that MMP-9 promoter sequence from -446 bp to -1174 bp relative to start codon is responsive to RANKL stimulation. Sequence analysis of the mouse MMP-9 gene promoter region further identified the presence of binding motif (-1123 bp to -1153 bp) for the nuclear factor of activated T cells 1 (NFATc1) transcription factor. Inhibition of NFATc1 using siRNA and VIVIT peptide inhibitor significantly decreased RANKL stimulation of MMP-9 activity. We further confirm by oligonucleotide pull-down assay that RANKL stimuli enhanced NFATc1 binding to MMP-9 gene promoter element. In addition, over-expression of constitutively active NFAT in RAW264.7 cells markedly increased (5-fold) MMP-9 gene promoter activity in the absence of RANKL. Taken together, our results suggest that RANKL signals through TRAF6 and that NFATc1 is a downstream effector of RANKL signaling to modulate MMP-9 gene expression during osteoclast differentiation.

RANK ligand signaling modulates the matrix metalloproteinase-9 gene expression during osteoclast differentiation. Publishing Authors By Initials

K Sundaram,R Nishimura,J Senn,RF Youssef,SD London,SV Reddy,

For similar peptides: intracellular signaling peptides and proteins: adaptor proteins, signal transducing: tumor necrosis factor receptor-associated peptides and proteins: tnf receptor-associated factor 6 research abstracts see: peptides: intracellular signaling peptides and proteins: adaptor proteins, signal transducing: tumor necrosis factor receptor-associated peptides and proteins: tnf receptor-associated factor 6 research

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RANK ligand signaling modulates the matrix metalloproteinase-9 gene expression during osteoclast differentiation. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Experimental cell research

VOLUME: 313

Page Numbers: 168-78

Journal Abbreviation: Exp. Cell Res.

ISSN: 0014-4827

DAY: 6

MONTH: 10

YEAR: 2006

RANK ligand signaling modulates the matrix metalloproteinase-9 gene expression during osteoclast differentiation. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 373226

RANK ligand signaling modulates the matrix metalloproteinase-9 gene expression during osteoclast differentiation. Keywords Mesh Terms:

KEYWORDS: TNF Receptor-Associated Factor 6

MESH TERMS: metabolism

Chemical & Substance for Abstract: RANK ligand signaling modulates the matrix metalloproteinase-9 gene expression during osteoclast differentiation. Information

Substance Name: Matrix Metalloproteinase 9

Registry Number: EC 3.4.24.35

Grant and Affiliation Information for RANK ligand signaling modulates the matrix metalloproteinase-9 gene expression during osteoclast differentiation.

AFFILIATION: Charles P. Darby Children's Research Institute, 173 Ashley Avenue, Charleston, SC 29425, USA.

Country: United States

AGENCY: United States NIDCR

GRANT: DE 12603

ACRONYM: DE

MEDLINETA: Exp Cell Res

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